Dual high-frequency difference excitation for contrast detection

Stimulating high-frequency nonlinear oscillations of ultrasound contrast agents is helpful to distinguish microbubbles from background tissues. Nevertheless, inefficiency of such oscillations from most commercially available contrast agents and intense attenuation of the resultant high-frequency harmonics limit microbubble detection with high-frequency ultrasound. To avoid this high-frequency nature, we devised and explored a dual-frequency difference excitation technique to induce efficiently low-frequency, rather than high-frequency, nonlinear scattering from microbubbles by using high-frequency ultrasound. The proposed excitation pulse is comprised of 2 high-frequency sinusoids with frequency difference subject to the microbubble resonance frequency. Its envelope, with frequency being the difference between the 2 frequencies, is used to stimulate nonlinear oscillation of microbubbles for the consonant low-frequency harmonic generation, whereas high-imaging resolution is retained because of narrow high-frequency transmit beams. Hydrophone measurements and phantom experiments of speckle-generating flow phantoms were performed to demonstrate the efficacy of the proposed technique. The results show that, especially when the envelope frequency is near the microbubbleiquests resonance frequency, the envelope of the proposed excitation pulse can induce significant nonlinear scattering from microbubbles, the induced nonlinear responses tend to increase with the pulse pressures, and up to 26 dB and 36 dB contrast-to-tissue ratios with second- and fourth-order nonlinear responses, respectively, can be obtained. Potential applications of this method include microbubble fragmentation and cavitation with high-frequency ultrasound.     

Techniques for perfusion imaging with microbubble contrast agents

The acoustic properties of ultrasound contrast agents vary widely with agent composition and insonation conditions. For contrast imaging, methods are required to match RF and Doppler processing to each combination of transmission parameters and agent and tissue properties. We propose a method that uses the measured or modeled echoes from agent and tissue to specify directly the characteristics of RF and Doppler filters for contrast imaging. The proposed method is sufficiently general to cover most common imaging techniques including harmonic greyscale, Doppler, and pulse inversion imaging. Using this method, sample filters were designed to detect myocardial perfusion with the contrast agent Optison^TM (Mallinckrodt Medical, St. Louis, MO) under selected imaging conditions. Simplified power Doppler filtering, using a weighted sum of the Doppler samples, matched the performance of more complicated matrix filters. By coordinating the selection of RF and Doppler filters rather than designing these filters sequentially, agent-to-tissue contrast was increased by up to 3.9 dB. Under some conditions, fundamental RF filtering outperformed harmonic filtering for intermittent Doppler imaging     

Second harmonic imaging and harmonic Doppler measurements withAlbunex

Gaseous ultrasound contrast agents, such as Albunex, have been shown to be valuable clinically for the better identification of certain anatomic structures and for quantitating organ perfusion. However, the application of a contrast agent sometimes also reduces the image contrast between the blood and the surrounding tissues. This paper presents experimental results to show that this problem may be alleviated by using harmonic signals generated by nonlinear backscattering of these microbubbles. The results show that the second harmonic signal produced by Albunex is significant and that harmonic images in which backscattered echoes from solid tissues were filtered out, but not those from Albunex, can be obtained. In addition, a continuous wave Doppler arrangement has been implemented. It permits quantitative harmonic Doppler measurements at different frequencies, concentrations, and transmitted acoustic pressures. When Albunex was compared to polystyrene microsphere suspensions which possess exclusively linear behavior, Doppler power at second and subharmonic frequencies could only be detected from these microbubbles. A comparison of results on Doppler powers measured at the first harmonic from polystyrene spheres and Albunex indicates that at a transmitting frequency of 2.5 MHz, the Doppler power from Albunex is 12 dB stronger than the polystyrene spheres, whereas at 5 MHz, the Doppler power from Albunex is 3 dB weaker than that from the polystyrene spheres     

Golay pulse encoding for microbubble contrast imaging in ultrasound

We present a technique that uses Golay phase encoding, pulse inversion, and amplitude modulation (GPIAM) for microbubble contrast agent imaging with ultrasound. This technique improves the contrast-to-tissue ratio (CTR) by increasing the time-bandwidth product of the insonating waveforms. A nonlinear pulse compression algorithm is used to compress the signal energy upon receive. A 6.5-dB improvement in CTR was observed using an 8-chip GPIAM sequence compared to a conventional pulse-inversion amplitude-modulation sequence. The CTR improvement comes at the cost of a reduction in frame rate: GPIAM coding uses four input pulses whereas most contrast imaging sequences require two or three pulses. Our results showed that the microbubble response can be phase encoded and subsequently compressed using a nonlinear matched-filtering algorithm, in order to enhance the signal from the contrast agent, while maintaining resolution and suppressing the tissue signal.     

A new ultrasound contrast imaging approach based on the combination of multiple imaging pulses and a separate release burst

A new ultrasound contrast imaging technique is described that optimally employs the rupture of the contrast agent. It is based on a combination of multiple high frequency, broadband, imaging pulses and a separate release burst. The imaging pulses are used to survey the target before and after the rupture and release of free gas bubbles. In this way, both processes (imaging and release) can be optimized separately. The presence of the contrast agent is simply detected by correlating or subtracting the signal responses of the imaging pulses. Because the time delay between the imaging pulses can be very short, the subtraction is less affected by tissue motion and can be done in real time. In vitro measurements showed that by using a release burst, the detection sensitivity increased 12 to 43 dB for different types of contrast agents. In the presence of a moving phantom, the increase in sensitivity was 22 dB. This new method is very sensitive for contrast agent detection in fundamental imaging mode and, therefore, non-linear propagation effects do not limit the maximum obtainable agent-to-tissue ratio. However, because of the inherent destruction of the contrast agent, it has to operate in an intermittent way. Through experiments, we have demonstrated the potential of the method to achieve simultaneous high sensitivity for contrast detection, i.e., high agent-to-tissue ratio, and high spatial resolution performance for different types of contrast agents     

Contrast imaging by non-overlapping dual frequency band transmit pulse complexes

SURF contrast imaging, as described previously in the literature, is a contrast agent detection technique achieved by processing of the received signals from transmitted dual frequency band pulse complexes with overlapping high-frequency (HF) and low-frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the scattering properties of the contrast agent. As with harmonic contrast agent detection techniques, nonlinear wave propagation will, in most situations, also limit the specificity with the SURF contrast technique when transmitting overlapping HF and LF pulses. The present paper proposes an alternative SURF contrast imaging technique using transmit dual frequency band pulse complexes with non-overlapping HF and LF pulses. If the frequency of the LF manipulation pulse is close to the bubble resonance frequency, numerical simulations indicate a significant ring-down effect of the LF bubble radius response. Utilizing this bubble ring-down effect and transmitting the HF pulse just after the LF pulse, a contrast agent specificity approaching infinity accompanied by a contrast agent sensitivity only for contrast bubbles having resonance frequencies within a narrow frequency range may be obtained.     

Comparison of pulse subtraction Doppler and pulse inversion Doppler

In this paper, a new Doppler technique based on pulse subtraction imaging (PSD) is described and compared with pulse inversion Doppler (PID). Combining a nonlinear contrast agent imaging technique with a Doppler process provides a tool for detecting motion of both contrast agents and tissues. This has potential in targeted imaging in which attached microbubbles need to be separated from moving ones and surrounding tissues. The results from both simulation and experiment show that PSD is able to differentiate bubble motion from tissue motion. For Doppler processing conducted at the fundamental frequency, the contrast-to-tissue ratio (CTR) in PSD was 3.3 (±0.4) times higher on average than PID at a mechanical index (MI) of 0.1. At the harmonic frequency, PID was shown to have a 3.1 (±0.4) times higher CTR than PSD. Overall, taken in their optimum processing conditions, PID has a CTR up to 1.9 (±0.4) times higher than PSD. The CTRs for both techniques have also been shown to increase with increasing MI. However, for the same axial Doppler resolution. PSD also allows less energy to be transmitted into the medium, which makes it less disruptive. The relative performances of PSD and PID in terms of the bandwidth of the imaging system are also discussed.     

Pulse inversion sequences for mechanically scanned transducers

Mechanically scanned transducers are currently used for tissue harmonic imaging (THI) and nonlinear microbubble imaging at high frequencies. The pulse inversion (PI) technique is widely used for suppressing the fundamental signal, but its effectiveness is reduced by relative tissue/ transducer motion. In this paper, we investigate multipulse inversion (MPI) sequences that achieve a significant improvement on the fundamental suppression for mechanically scanned single-element transducers. MPI was subsequently applied on simulated and measured RF-data and relative fundamental suppression was compared with the 2-pulse PI technique. Simulations showed, for example, an increased fundamental suppression of 6 and 10 dB for MPI-sequences that combined 3 and 7 pulses, respectively, for a rotating intravascular ultrasound transducer with an interpulse angle of 0.15deg. Initial application of MPI sequences on RF-data from in vivo acquisitions resulted in similar fundamental suppression levels. The investigated MPI technique will help to reduce relative tissue/transducer motion effects and might lead to improved sensitivity and spatial resolution in nonlinear tissue imaging and improved microbubble detection in contrast imaging for mechanically scanned transducers.     

Pulse subtraction time delay imaging method for ultrasound contrast agent detection

Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.     

Subharmonic emissions from microbubbles: effect of the driving pulse shape

The aims of this work are to investigate the response of the ultrasonic contrast agents (UCA) insonified by different arbitrary-shaped pulses at different acoustic pressures and concentration of the contrast agent focusing on subharmonic emission. A transmission setup was developed in order to insonify the contrast agent contained in a measurement chamber. The transmitted ultrasonic signals were generated by an arbitrary wave generator connected to a linear power amplifier able to drive a single-element transducer. The transmitted ultrasonic pulses that passed through the contrast agent-filled chamber were received by a second transducer or a hydrophone aligned with the first one. The radio frequency (RF) signals were acquired by fast echographic multiparameters multi-image novel apparatus (FEMMINA), which is an echographic platform able to acquire ultrasonic signals in a real-time modality. Three sets of ultrasonic signals were devised in order to evaluate subharmonic response of the contrast agent respect with sinusoidal burst signals used as reference pulses. A decreasing up to 30 dB in subharmonic response was detected for a Gaussian-shaped pulse; differences in subharmonic emission up to 21 dB were detected for a composite pulse (two-tone burst) for different acoustic pressures and concentrations. Results from this experimentation demonstrated that the transmitted pulse shape strongly affects subharmonic emission in spite of a second harmonic one. In particular, the smoothness of the initial portion of the shaped pulses can inhibit subharmonic generation from the contrast agents respect with a reference sinusoidal burst signal. It also was shown that subharmonic generation is influenced by the amplitude and the concentration of the contrast agent for each set of the shaped pulses. Subharmonic emissions that derive from a nonlinear mechanism involving nonlinear coupling among different oscillation modes are strongly affected by the shape of the ultrasonic driving pulse.     

High frequency nonlinear B-scan imaging of microbubble contrast agents

It was previously shown that it is possible to produce nonlinear scattering from microbubble contrast agents using transmit frequencies in the 14-32 MHz range, suggesting the possibility of performing high-frequency, nonlinear microbubble imaging. In this study, we describe the development of nonlinear microbubble B-scan imaging instrumentation capable of operating at transmit center frequencies between 10 and 50 MHz. The system underwent validation experiments using transmit frequencies of 20 and 30 MHz. Agent characterization experiments demonstrate the presence of nonlinear scattering for the conditions used in this study. Using wall-less vessel phantoms, nonlinear B-scan imaging is performed using energy in one of the subharmonic, ultraharmonic, and second harmonic frequency regions for transmit frequencies of 20 and 30 MHz. Both subharmonic and ultraharmonic imaging modes achieved suppression of tissue signals to below the noise floor while achieving contrast to noise ratios of up to 26 and 17 dB, respectively. The performance of second harmonic imaging was compromised by nonlinear propagation and offered no significant contrast improvement over fundamental mode imaging. In vivo experiments using the subharmonic of a 20 MHz transmit pulse show the successful detection of microvessels in the rabbit ear and in the mouse heart. The results of this study demonstrate the feasibility of nonlinear microbubble imaging at high frequencies     

Harmonic leakage and image quality degradation in tissue harmonic imaging

Image quality degradation caused by harmonic leakage was studied for finite amplitude distortion-based harmonic imaging. Various sources of harmonic leakage, including transmit waveform, signal bandwidth, and system nonlinearity, were investigated using both simulations and hydrophone measurements. Effects of harmonic leakage in the presence of sound velocity inhomogeneities were also considered. Results indicated that sidelobe levels of the harmonic beam pattern were directly affected by harmonic leakage when the harmonic signal was obtained by filtering out the fundamental signal. Because sidelobe levels also increase with the bandwidth of the transmitted signal, a trade-off exists between axial resolution and contrast resolution. It is concluded that accurate control of the frequency content of the waveform prior to propagation is necessary to optimize imaging performance of tissue harmonic imaging. The filtering technique was also compared with the pulse inversion technique. It was shown that the pulse inversion technique effectively suppresses harmonic leakage at the cost of imaging frame rate and potential motion artifacts     

Broadband PVDF membrane hydrophone for comparisons of hydrophone calibration methods up to 140 MHz

A PVDF membrane hydrophone has been constructed in particular for comparisons of broadband ultrasound hydrophone calibration methods and of the results obtained by different laboratories. Intercomparisons have to accompany the efforts currently undertaken to enhance the calibration frequency ranges and to implement the extension from the determination of amplitude-only to complex-valued calibration data. It can be expected that such hydrophone data will be used much more frequently in the future for exposure measurements on medical ultrasound equipment, in particular for the detection of nonlinearly distorted waveforms. The hydrophone design chosen has a foil thickness of 9 microm and an electrode diameter of 210 microm. A broadband differential preamplifier (-3 dB roll-off frequency: 95 MHz) is integrated to achieve a high signal-to-noise ratio over a broad frequency range (e.g., 26 dB-30 dB in the range 50 MHz to 140 MHz for measurements of nonlinearly distorted pulses). The hydrophone response was characterized by means of a primary interferometric calibration technique, by substitution calibration using time-delay spectrometry, and by complex broadband pulse calibration using nonlinear sound propagation. The results show a flat frequency response up to 40 MHz (maximum variations below +/-0.6 dB) and a thickness mode resonance at about 105 MHz. They indicate a useable bandwidth up to 140 MHz. The effective diameter as derived from directional response measurements is 240 microm at frequencies beyond 15 MHz.     

Contrast imaging with chirped excitation

Coded excitation has been successfully used in imaging to increase the signal-to-noise ratio (SNR) and penetration depth. With a contrast agent, wideband signals have been hypothesized to increase the contrast-to-tissue ratio (CTR). However, nonlinear properties of contrast agents make decoding difficult when applying coded excitation to contrast imaging. We propose two chirped excitation methods to image contrast agents, with a mechanical index (MI) ranging from 0.05 to 0.34. In the single chirp method, one chirp is transmitted, followed by a clutter filter to reject tissue echoes, then a matched filter is used to recover range resolution. In the chirp sequence method, an increasing and decreasing chirp sequence is transmitted followed by subtraction of the compressed echoes to reject tissue echoes (assuming tissue is a linear scatterer at low MI). Ten independent acoustic experiments were performed to evaluate the CTR for chirp and tone burst insonation, with the same spatial peak temporal averaged intensity (I(SPTA)). A significant increase in CTR, ranging from 4 dB to 8 dB, is observed for chirped excitation as compared with tone burst insonation, at an I(SPTA) of 0.1 and 0.3 mW/cm2 (P < or = 5e-3). To achieve the same CTR of 15 dB, the spatial peak pulse averaged intensity (I(SPPA)) can be decreased by 6 dB for chirp insonation as compared with tone burst insonation (P < 1e-5). Additionally, an increase of more than 10 dB in tissue rejection ratio (TRR) is observed for a chirp sequence insonation compared to tone burst phase inversion for this set of parameters (P < or = 1e-9). Deconvolution of the linear microbubble response from the received echoes is proposed as a method to recover spatial resolution. The difference in the axial resolution resulting from chirp and three-cycle tone burst insonation is approximately 220 microm. The difference in the mainlobe width between experimental and predicted compressed echoes is less than 20%. The side-lobe amplitude is 9 dB to 16 dB below the mainlobe with a transmitted I(SPTA) from 0.1 to 6.6 mW/cm2.     

Motion artifacts of pulse inversion-based tissue harmonic imaging

Motion artifacts of the pulse inversion technique were studied for finite amplitude distortion-based harmonic imaging. Motion in both the axial and the lateral directions was considered. Two performance issues were investigated. One is the harmonic signal intensity relative to the fundamental intensity and the other is the potential image quality degradation resulting from spectral leakage. A one-dimensional (1-D) correlation-based correction scheme also was used to compensate for motion artifacts. Results indicated that the tissue harmonic signal is significantly affected by tissue motion. For axial motion, the tissue harmonic intensity decreases much more rapidly than with lateral motion. The fundamental signal increases for both axial and lateral motion. Thus, filtering is still required to remove the fundamental signal, even if the pulse inversion technique is applied. The motion also potentially decreases contrast resolution because of the uncancelled spectral leakage. Also, it was indicated that 1-D motion correction is not adequate if nonaxial motion is present.     

Acoustic signatures of submicron contrast agents

Previous studies have revealed that hard-shelled submicron contrast agents exhibit large relative expansions and strong acoustical echoes that can be observed experimentally, and predicted by theoretical simulations. In this paper, we study harmonic imaging and pulse-pair imaging techniques designed to assist in the differentiation of these contrast agents from tissue. For harmonic imaging, we apply a high-sensitivity, narrowband strategy that differentiates the microbubble from tissue based on the generation of strong harmonic echoes. For pulse-pair imaging, we apply high spatial resolution, wideband strategies using phase inversion, which relies on the frequency differences observed in response to phase-inverted pulses, and signal subtraction, which takes advantage of the amplitude differences in response to identical pulses. The bubble-to-phantom signal amplitude ratio in the absence of motion approaches 20 dB using phase inversion and 30 dB using signal subtraction; both techniques are robust for up to 50 microm of simulated motion. With the experience gained in these studies, we hope to advance the development of multi-pulse or shaped-pulse techniques that are optimized for specific clinical applications.     

SURF imaging for contrast agent detection

A contrast agent detection method is presented that potentially can improve the diagnostic significance of ultrasound contrast agents. Second order ultrasound field (SURF) contrast imaging is achieved by processing the received signals from transmitted dual frequency band pulse complexes with overlapping high-frequency (HF) and low-frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the scattering properties of the contrast agent. In the present paper, we discuss how SURF contrast imaging potentially can overcome problems and limitations encountered with available contrast agent detection methods, and we give a few initial examples of in vitro measurements. With SURF contrast imaging, the resonant properties of the contrast agent may be decoupled from the HF imaging pulses. This technique is thus especially interesting for imaging contrast bubbles above their resonance frequency. However, to obtain adequate specificity, it is typically necessary to estimate and correct for accumulative nonlinear effects in the forward wave propagation.     

Bandwidth and resolution enhancement through pulse compression

A novel pulse compression technique is developed that improves the axial resolution of an ultrasonic imaging system and provides a boost in the echo signal-to-noise ratio (eSNR). The new technique, called the resolution enhancement compression (REC) technique, was validated with simulations and experimental measurements. Image quality was examined in terms of three metrics: the eSNR, the bandwidth, and the axial resolution through the modulation transfer function (MTF). Simulations were conducted with a weakly-focused, single-element ultrasound source with a center frequency of 2.25 MHz. Experimental measurements were carried out with a single-element transducer (f/3) with a center frequency of 2.25 MHz from a planar reflector and wire targets. In simulations, axial resolution of the ultrasonic imaging system was almost doubled using the REC technique (0.29 mm) versus conventional pulsing techniques (0.60 mm). The -3 dB pulse/echo bandwidth was more than doubled from 48% to 97%, and maximum range sidelobes were -40 dB. Experimental measurements revealed an improvement in axial resolution using the REC technique (0.31 mm) versus conventional pulsing (0.44 mm). The -3 dB pulse/echo bandwidth was doubled from 56% to 113%, and maximum range sidelobes were observed at -45 dB. In addition, a significant gain in eSNR (9 to 16.2 dB) was achieved.     

Suppression of propagating second harmonic in ultrasound contrast imaging

Contrast agents, such as bubbles, are used in ultrasound to enhance backscatter from blood. To increase contrast between these agents and tissue, nonlinear methods such as harmonic imaging can be used. Contrast is limited, however, by tissue second harmonic signals. We show that a major source of this signal is nonlinear propagation through tissue. In addition, we present methods to suppress this second harmonic generation. One simple approach is to decrease the f/number of the imaging system. Simulations show that doubling the size of the array, while keeping total power output constant, decreases propagating second harmonic generation. A second approach uses active noise cancellation to suppress second harmonic generation. A specific method, the harmonic cancellation system (HCS), is developed and presented as an example. In simulations, HCS decreased second harmonic generation by over 30 dB. Using such methods, contrast can be improved between tissue and bubbles in harmonic imaging.     

The diagonalized contrast source inversion approach for elastic wave inversion

This study focuses on the inverse scattering of objects embedded in a homogeneous elastic background. The medium is probed by ultrasonic sources, and the scattered fields are observed along a receiver array. The goal is to retrieve the shape, location, and constitutive parameters of the objects through an inversion procedure. The problem is formulated using a vector integral equation. As is well-known, this inverse scattering problem is nonlinear and ill-posed. In a realistic configuration, this nonlinear inverse scattering problem involves a large number of unknowns, hence the application of full nonlinear inversion approaches such as Gauss-Newton or nonlinear gradient methods might not be feasible, even with present-day computer power. Hence, in this study we use the so-called diagonalized contrast source inversion (DCSI) method in which the nonlinear problem is approximately transformed into a number of linear problems. We will show that, by using a three-step procedure, the nonlinear inverse problem can be handled at the cost of solving three constrained linear inverse problems. The robustness and efficiency of this approach is illustrated using a number of synthetic examples.